EP2858499B1 - Pyrimidinyl tyrosine kinase inhibitors - Google Patents

Pyrimidinyl tyrosine kinase inhibitors Download PDF

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Publication number
EP2858499B1
EP2858499B1 EP13800042.7A EP13800042A EP2858499B1 EP 2858499 B1 EP2858499 B1 EP 2858499B1 EP 13800042 A EP13800042 A EP 13800042A EP 2858499 B1 EP2858499 B1 EP 2858499B1
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Prior art keywords
compound
amino
chloro
bipiperidine
oxo
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EP13800042.7A
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German (de)
English (en)
French (fr)
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EP2858499A4 (en
EP2858499A1 (en
Inventor
Brian T. Hopkins
Patrick Conlon
Timothy R. CHAN
Tracy J. Jenkins
Xiongwei Cai
Michael Humora
Xianglin Shi
Ross A. Miller
Andrew Thompson
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Biogen MA Inc
Viracta Therapeutics Inc
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Sunesis Pharmaceuticals Inc
Biogen MA Inc
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Priority to RS20180950A priority Critical patent/RS57978B1/sr
Priority to SI201331130T priority patent/SI2858499T1/sl
Priority to EP20186539.1A priority patent/EP3753934A1/en
Priority to EP18171833.9A priority patent/EP3385263B1/en
Priority to PL13800042T priority patent/PL2858499T3/pl
Application filed by Sunesis Pharmaceuticals Inc, Biogen MA Inc filed Critical Sunesis Pharmaceuticals Inc
Publication of EP2858499A1 publication Critical patent/EP2858499A1/en
Publication of EP2858499A4 publication Critical patent/EP2858499A4/en
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Publication of EP2858499B1 publication Critical patent/EP2858499B1/en
Priority to HRP20181294TT priority patent/HRP20181294T1/hr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics

Definitions

  • the Tec kinases are non-receptor tyrosine kinases including: Tec (tyrosine kinase expressed in hepatocellular carcinoma), Btk (Bruton's tyrosine kinase), Itk (interleukin-2 (IL-2)-inducible T-cell kinase; also known as Emt or Tsk), Rlk (resting lymphocyte kinase; also known as Txk), Lck (lymphocyte-specific protein tyrosine kinase), and Bmx (bone-marrow tyrosine kinase gene on chromosome X; also known as Etk)).
  • Tec tyrosine kinase expressed in hepatocellular carcinoma
  • Btk Brun's tyrosine kinase
  • Itk interleukin-2 (IL-2)-inducible T-cell kinase
  • Rlk resting lymphocyte kinas
  • Tec kinases are primarily expressed in haematopoietic cells, although expression of Bmx and Tec has been detected in endothelial and liver cells.
  • Tec kinases (Itk, Rlk and Tec) are expressed in T cells and are all activated downstream of the T-cell receptor (TCR).
  • Btk is a downstream mediator of B cell receptor (BCR) signaling which is involved in regulating B cell activation, proliferation, and differentiation. More specifically, Btk contains a PH domain that binds phosphatidylinositol (3,4,5)-trisphosphate (PIP3).
  • PIP3 binding induces Btk to phosphorylate phospholipase C (PLC ⁇ ), which in turn hydrolyzes PIP2 to produce two secondary messengers, inositol triphosphate (IP3) and diacylglycerol (DAG), which activate protein kinase PKC, which then induces additional B-cell signaling.
  • IP3 inositol triphosphate
  • DAG diacylglycerol
  • Mutations that disable Btk enzymatic activity result in XLA syndrome (X-linked agammaglobulinemia), a primary immunodeficiency.
  • Tec kinases are targets of interest for autoimmune disorders.
  • Compounds useful as inhibitors for Btk are disclosed, for example in WO 2011/029046 .
  • the present invention provides a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein R 1 and Ring A are as defined in claim 1.
  • Such compounds are inhibitors of the Tec kinase family, including Btk. Accordingly, provided compounds can be used in a variety of methods including in vitro screening and activity assays as well as in vivo pre-clinical, clinical, and therapeutic settings, as described in detail herein.
  • the present invention provides pharmaceutical formulations comprising provided compounds.
  • the present invention provides compounds for use in a method of decreasing enzymatic activity of Btk.
  • the present invention provides compounds for use in a method of treating a disorder responsive to Btk inhibition in a subject in need thereof. Such disorders and methods are described in detail herein.
  • the present invention provides a compound of formula I: or a pharmaceutically acceptable salt thereof; wherein:
  • aliphatic or "aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-6 aliphatic carbon atoms.
  • aliphatic groups contain 1-5 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • cycloaliphatic refers to a monocyclic C 3 -C 6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • heterocycle As used herein, the terms “heterocycle,” “heterocyclyl,” and “heterocyclic ring” are used interchangeably and refer to a stable 3- to 7-membered monocyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen When used in reference to a ring atom of a heterocycle, the term “nitrogen” includes a substituted nitrogen.
  • heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19 .
  • the neutral forms of the compounds are regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
  • the present invention provides a compound of formula I : of a pharmaceutically acceptable salt thereof, wherein R 1 and Ring A are as defined in claim 1.
  • one R 1 is hydrogen or and the other R 1 is C 1-6 aliphatic. In some embodiments, one R 1 is hydrogen and the other R 1 is methyl. In some embodiments, one R 1 is hydrogen and the other R 1 is ethyl. In some embodiments, one R 1 is hydrogen and the other R 1 is C1 -6 (cycloalkyl)alkyl. In some embodiments, one R 1 is hydrogen and the other R 1 is C 1-6 (cycloalkyl).
  • one R 1 is hydrogen and the other R 1 is C 1-6 aliphatic optionally substituted with -OR, wherein R is hydrogen or C 1-6 aliphatic.
  • one R 1 is hydrogen and the other R 1 is a heterocyclylalkyl group having 3-7 carbon atoms and 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, one R 1 is hydrogen and the other R 1 is an optionally substituted 3-7 membered monocyclic heterocycle.
  • two R 1 groups are taken together with their intervening atoms to form an optionally substituted 3-5 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, two R 1 groups are taken together with their intervening atoms to form an optionally substituted piperazine ring.
  • Ring A is
  • R 2 is -Cl. In other embodiments, R 2 is -F. In some embodiments, R 3 is -CF 3 . In some embodiments, R 3 is -OCF 3 . In some embodiments, R 3 is -F.
  • Ring A is selected from the group consisting of:
  • the present invention provides a compound of formula II-a : or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , and R 3 is as defined above and described in classes and subclasses herein.
  • the present invention provides a compound of formula II-b: or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , and R 3 is as defined above and described in classes and subclasses herein.
  • the present invention provides a compound of formula III: or a pharmaceutically acceptable salt thereof, wherein each of R 2 and R 3 is as defined above and described in classes and subclasses herein.
  • the present invention provides a compound of formula IV: or a pharmaceutically acceptable salt thereof, wherein each of R 1 and R 3 is as defined above and described in classes and subclasses herein. In some embodiments, both R 1 are hydrogen. In some embodiments, one R 1 is hydrogen and the other R 1 is methyl.
  • the PG, PG 1 , PG 2 , and PG 3 groups of compounds in Schemes 1 through 5a are each independently a suitable protecting group.
  • suitable protecting group Such ester and amine protecting groups are known in the art and are described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999 .
  • a protecting group is a Boc group.
  • each of the synthetic steps in Schemes 1 through 5a may be performed sequentially with isolation of each intermediate performed after each step.
  • each of the steps as depicted in Schemes 1, 2, 3, and 4 above may be performed in a manner whereby no isolation of one or more intermediates is performed.
  • all the steps of the aforementioned synthesis may be performed to prepare the desired final product. In other embodiments, two, three, four, five, or more sequential steps may be performed to prepare an intermediate or the desired final product.
  • Tec kinase family member refers to any non-receptor tyrosine kinase in the Tec kinase family.
  • Tec kinase family members are Tec, Btk, Itk, Txk, Lck, and Bmx.
  • the present invention provides compounds for use in a method of decreasing Btk enzymatic activity.
  • such uses include contacting a Btk with an effective amount of a Btk inhibitor. Therefore, the present invention further provides compounds for use in a method of inhibiting Btk enzymatic activity by contacting a Btk with a Btk inhibitor of the present invention.
  • Btk enzymatic activity refers to Btk kinase enzymatic activity.
  • the half maximal inhibitory concentration (IC 50 ) of the Btk inhibitor against Btk is less than 1 ⁇ M.
  • the IC 50 of the Btk inhibitor against Btk is less than 500 nM.
  • the IC 50 of the Btk inhibitor against Btk is less than 100 nM.
  • the IC 50 of the Btk inhibitor against Btk is less than 10 nM.
  • the IC 50 of the Btk inhibitor against Btk is less than 1 nM. In some embodiments, the IC 50 of the Btk inhibitor against Btk is from 0.1 nM to 10 ⁇ M. In some embodiments, the IC 50 of the Btk inhibitor against Btk is from 0.1 nM to 1 ⁇ M. In some embodiments, the IC 50 of the Btk inhibitor against Btk is from 0.1 nM to 100 nM. In some embodiments, the IC 50 of the Btk inhibitor against Btk is from 0.1 nM to 10 nM.
  • autoimmune disorders includes diseases or disorders involving inappropriate immune response against native antigens, such as acute disseminated encephalomyelitis (ADEM), Addison's disease, alopecia areata, antiphospholipid antibody syndrome (APS), hemolytic anemia, autoimmune hepatitis, bullous pemphigoid (BP), Coeliac disease, dermatomyositis, diabetes mellitus type 1, Good Pasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, lupus or systemic lupus erythematosus (SLE), mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, hemophilia with inhibitors, pernicious anaemia, polymyositis, primary biliary cirrhosis, Sjögren's syndrome, temporal arteritis, and Wegener
  • inflammatory disorders includes diseases or disorders involving acute or chronic inflammation such as allergies, asthma (e.g., allergic asthma), atopic dermatitis, prostatitis, glomerulonephritis, pelvic inflammatory disease (PID), inflammatory bowel disease (IBD, e.g., Crohn's disease, ulcerative colitis), reperfusion injury, rheumatoid arthritis, transplant rejection (including transplant patients with a positive cross-match) and vasculitis.
  • asthma e.g., allergic asthma
  • atopic dermatitis e.g., prostatitis, glomerulonephritis, pelvic inflammatory disease (PID)
  • IBD inflammatory bowel disease
  • transplant rejection including transplant patients with a positive cross-match
  • vasculitis e.g., vasculitis.
  • the present invention provides methods of treating disease, disorders, or conditions that approved for treatment with rituximab (a monoclonal antibody against CD20), including non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), RA, Wegener's granulomatosis (WG), and microscopic polyangiitis (MPA).
  • rituximab a monoclonal antibody against CD20
  • NDL non-Hodgkin's lymphoma
  • CLL chronic lymphocytic leukemia
  • WG Wegener's granulomatosis
  • MPA microscopic polyangiitis
  • the present invention provides a method of treating rheumatoid arthritis (RA), SLE, or atopic dermatitis using compounds disclosed herein.
  • cancer includes diseases or disorders involving abnormal cell growth and/or proliferation, such as glioma, thyroid carcinoma, breast carcinoma, lung cancer (e.g. small-cell lung carcinoma, non-small-cell lung carcinoma), gastric carcinoma, gastrointestinal stromal tumors, pancreatic carcinoma, bile duct carcinoma, ovarian carcinoma, endometrial carcinoma, prostate carcinoma, renal cell carcinoma, lymphoma (e.g., anaplastic large-cell lymphoma), leukemia (e.g. acute myeloid leukemia, T-cell leukemia, chronic lymphocytic leukemia), multiple myeloma, malignant mesothelioma, malignant melanoma, and colon cancer (e.g. microsatellite instability-high colorectal cancer).
  • the present invention provides a method of treating leukemia or lymphoma.
  • subject refers to a mammal to whom a pharmaceutical composition is administered.
  • exemplary subjects include humans, as well as veterinary and laboratory animals such as horses, pigs, cattle, dogs, cats, rabbits, rats, mice, and aquatic mammals.
  • provided compounds are useful for the treatment of disease, including RA and SLE. As described in more detail below, these diseases are affiliated with B cells. Thus, the present disclosure encompasses the recognition that provided compounds are useful as therapeutics for these and other indications.
  • Dysregulation of the immune system is central to the pathogenesis ( Panayi GS, et al. Rheum Dis Clin North Am 2001; 27:317-334 ) of RA. While most of the infiltrating leukocytes in the synovium are T lymphocytes (primarily activated CD4+ T cells) and cells of monocyte/macrophage origin (which release pro-inflammatory cytokines such as IL-1, TNF-alpha and IL-6 and proteolytic enzymes including collagenases and metalloproteinases), B-cells and plasma cells are also found in the synovial fluid ( Zhang Z, Bridges SL. Rheum Dis Clin North Am 2001; 27:335-353 ).
  • T lymphocytes primarily activated CD4+ T cells
  • monocyte/macrophage origin which release pro-inflammatory cytokines such as IL-1, TNF-alpha and IL-6 and proteolytic enzymes including collagenases and metalloproteinases
  • B-cells and plasma cells are
  • Antibodies against nuclear components target nuclear antigens including DNA (typically double-stranded DNA [dsDNA]), RNA, histones and small nuclear ribonucleoproteins. These antibodies combine with self-antigens forming immune complexes which deposit in tissues, incite inflammatory reactions and lead to tissue injury.
  • B cells In addition to their roles in pathogenic autoantibody production, B cells also function as antigen-presenting cells (APCs) to T-cells thus playing a role in the initiation of an antigen-specific response. Given the central role of the humoral arm of the immune system in the pathogenesis of SLE, B cells or the B-cell pathway represent desirable therapeutic targets.
  • Belimumab a monoclonal antibody recently approved for SLE, blocks the binding BAFF to its receptors that are expressed B cells. These receptors serve to activate and potentiate the survival of B cells consistent with a reduction of circulating B cells observed following treatment with belimumab. See also Chan OT, et al. Immunol Rev. 1999b;169:107-121 ; Navarra SV, et al. Lancet. 2011 Feb 26;377(9767):721-31 ; Furie R, et al. Arthritis Rheum. 2011 Dec;63(12):3918-30 .
  • a compound of the present invention is administered in combination with another agent.
  • a compound of the present invention is useful for treating RA and is administered in combination with a disease-modifying antirheumatic drugs (DMARD), including without limitation: methotrexate, abatacept, azathioprine, certolizumab, chloroquine and hydroxychloroquine, cyclosporin, D-penicillamine, adalimumab, etanercept, golimumab, gold salts (including auranofin and sodium aurothiomalate), infliximab, leflunomide, minocycline, rituximab, sulfasalazine, tocilizumab, or combinations thereof.
  • DMARD disease-modifying antirheumatic drugs
  • a compound of the present invention is administered in combination with a NSAID or corticosteroid.
  • a compound of the present invention is useful for treating SLE and is administered in combination with an agent for the treatment of SLE, including without limitation: corticosteroids, antimalarials, belimumab, mycophenolate mofetil (MMF) or mycophenolate sodium, azathioprine, or combinations thereof.
  • an agent for the treatment of SLE including without limitation: corticosteroids, antimalarials, belimumab, mycophenolate mofetil (MMF) or mycophenolate sodium, azathioprine, or combinations thereof.
  • a compound of the present invention is useful for treating atopic dermatitis and is administered in combination with a topical agent for the treatment of atopic dermatitis, including without limitation: topical steroids, tacrolimus, methotrexate, mometasone furoate (MMF), azathioprine, retinoids, or combinations thereof.
  • a topical agent for the treatment of atopic dermatitis including without limitation: topical steroids, tacrolimus, methotrexate, mometasone furoate (MMF), azathioprine, retinoids, or combinations thereof.
  • candidate inhibitors capable of decreasing Tec kinase family enzymatic activity may be identified in vitro.
  • the activity of the inhibitor compounds can be assayed utilizing methods known in the art and/or those methods presented herein.
  • the compounds may be further tested for their ability to selectively inhibit a Tec kinase family member relative to other enzymes.
  • Compounds may be further tested in cell models or animal models for their ability to cause a detectable changes in phenotype related to a Tec kinase family member activity.
  • animal models may be used to test Tec kinase family member inhibitors for their ability to treat autoimmune disorders, inflammatory disorders, or cancer in an animal model.
  • compositions of the present invention may additionally include components to provide sustained release and/or comfort.
  • Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides, and finely-divided drug carrier substrates. These components are discussed in greater detail in U.S. Pat. Nos. 4,911,920 ; 5,403,841 ; 5,212,162 ; and 4,861,760 .
  • the dosage and frequency (single or multiple doses) of compound administered can vary depending upon a variety of factors, including route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated (e.g., the disease responsive to Btk inhibition); presence of other diseases or other health-related problems; kind of concurrent treatment; and complications from any disease or treatment regimen.
  • Other therapeutic regimens or agents can be used in conjunction with the methods and compounds of the invention.
  • the therapeutically effective amount can be initially determined from cell culture assays.
  • Target concentrations will be those concentrations of active compound(s) that are capable of decreasing kinase enzymatic activity as measured, for example, using the methods described.
  • Therapeutically effective amounts for use in humans may be determined from animal models.
  • a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals.
  • the dosage in humans can be adjusted by monitoring kinase inhibition and adjusting the dosage upwards or downwards, as described above.
  • the administered dose is in the range of about 10 mg to about 1000 mg per day, either once, twice, or more than twice daily.
  • Dosages may be varied depending upon the requirements of the patient and the compound being employed.
  • the dose administered to a patient should be sufficient to effect a beneficial therapeutic response in the patient over time.
  • the size of the dose also will be determined by the existence, nature, and extent of any adverse side effects.
  • treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached.
  • the dosage range is 0.001% to 10% w/v. In some embodiments, the dosage range is 0.1% to 5% w/v.
  • Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.
  • the aqueous layer was separated, cooled to 0 °C and neutralized with 3N HCl solution to pH between 7-8, while maintaining the internal temperature below 10°C.
  • the solution was washed with DCM (5 x 30 L) or until the LC/MS indicated no product 3-5 remained in the aqueous layer.
  • the combined organic layers were concentrated in vacuo to dryness, suspended in EtOAc and petroleum ether (2:1, 10 L) and stirred for 2 hours, the solids were filtered, washed by petroleum ether (5 L) and dried under vacuum at 50°C for 18 hours to give product (3.5 Kg, 53% yield) as a solid with 95% purity.
  • Compound 3-5 is a mixture of ⁇ 30:70 trans/cis at C-4 and ⁇ 93:7 R : S at C-3. The average overall yield from 3-1 is 43-55%.
  • the filtrate was concentrated in vacuo at 50 °C to a volume of ⁇ 200 mL. After cooled to 20 °C and stirred at this temperature for 2 hours, a slurry was obtained, and the solid was filtered, washed with water (400 mL) and dried under vacuum and at 50°C to give product 3-8 (65 g).
  • the wet cake from the reaction filtration was stirred in 1N HCl (1 L) for 2 hours to dissolve the product and the remaining catalyst solid was then removed by filtration.
  • the acidic filtrate was neutralized with solid LiOH to pH ⁇ 7 to precipitate the product 3-8.
  • the product was washed with water (200 mL), dried under vacuum and at 50°C to give 120 g of product.
  • the reaction was quenched by adding EtOH (35 mL) and stirring at 50 °C for 30 min. The mixture was heated at 75-85°C for 3 days. The mixture was cooled to 18 °C and transferred slowly into water (6 L) while vigorously stirring to afford a slurry. After 2 hours, the solids were filtered and washed with water (3 x 3 L), dried under vacuum at 60-70 °C for 24 hours to give 4-L-9 (114 g) as a brown solid. The solid was used directly in the subsequent step.
  • Peak 1 was further purified by SFC (AD-H (2 x 15cm), 30% MeOH (0.15% DEA)/CO 2 , 100 bar, 60 ml/min) to afford the titled compound.
  • the title compound was obtained from chiral separation of trans -1'-(6-amino-5-fluoropyrimidin-4-yl)-3-((3-chloro-5-(trifluoromethyl)phenyl) amino)- N , N -dimethyl-2-oxo-[1,3'-bipiperidine]-4'-carboxamide using a two step chiral SFC separation.
  • the mixture was separated into two peaks containg a mixture of two diastereomers ((3' R ,4' S )-1'-(6-amino-5-fluoropyrimidin-4-yl)-3-((3-chloro-5-(trifluoromethyl)phenyl)amino)- N , N -dimethyl-2-oxo-[1,3'-bipiperidine]-4'-carboxamide and (3' S ,4' R )-1'-(6-amino-5-fluoropyrimidin-4-yl)-3-((3-chloro-5 - (trifluoromethyl)phenyl)amino)- N , N -dimethyl-2-oxo-[1,3'-bipiperidine]-4'-carboxamide) using a ChiralPak IC(2 x 15 cm, 30% methanol w/0.1 DEA) column, and then the resulting mixture containing a pair of isomers was
  • the title compound was obtained from chiral separation of trans -1'-(6-amino-5-fluoropyrimidin-4-yl)-3-((3-chloro-5-(trifluoromethyl)phenyl)amino)- N , N -dimethyl-2-oxo-[1,3'-bipiperidine]-4'-carboxamide using a two step chiral SFC separation.
  • the mixture was separated into two peaks containg a mixture of two diastereomers ((3' R ,4' S )-1'-(6-amino-5-fluoropyrimidin-4-yl)-3-((3-chloro-5-(trifluoromethyl)phenyl)amino)- N,N -dimethyl-2-oxo-[1,3'-bipiperidine]-4'-carboxamide and (3' S ,4' R )-1'-(6-amino-5-fluoropyrimidin-4-yl)-3-((3-chloro-5 - (trifluoromethyl)phenyl)amino)- N , N -dimethyl-2-oxo-[1,3'-bipiperidine]-4'-carboxamide) using a ChiralPak IC(2 x 15 cm, 30% methanol w/0.1 DEA) column, and then the resulting mixture containing a pair of isomers was further
  • the mixture was separated into two peaks containg a mixture of two diastereomers ((3' R ,4' S )-1'-(6-amino-5-fluoropyrimidin-4-yl)-3-((3-chloro-5-(trif
  • the title compound was obtained from chiral separation of trans- 1' - (6-amino-5-fluoropyrimidin-4-yl)-3-((3-chloro-5-(trifluoromethyl)phenyl)amino)- N , N- ethyl-2-oxo-[1,3'-bipiperidine]-4'-carboxamide 23 using a two step chiral SFC separation.
  • the mixture was separated into two peaks containg a mixture of two diastereomers ((3' R ,4' S )-1'-(6-amino-5-fluoropyrimidin-4-yl) -3-((3-chloro-5-(trifluoromethyl)phenyl)amino)- N , N- dimethyl-2-oxo-[1,3'-bipiperidine]-4'-carboxamide and (3' S ,4' R )-1'-(6-amino-5-fluoropyrimidin-4-yl)-3-((3-chloro-5 - (trifluoromethyl)phenyl)amino)- N,N -dimethyl-2-oxo-[1,3'-bipiperidine]-4'-carboxamide) using a ChiralPak IC(2 x 15 cm, 30% methanol w/0.1 DEA) column, and then the resulting mixture containing a pair of isomers was further separated
  • the title compound was obtained from chiral separation of trans -1'-(6-amino-5-fluoropyrimidin-4-yl)-3-((3-chloro-5-(trifluoromethyl)phenyl)amino)- N,N -dimethyl-2-oxo-[1,3'-bipiperidine]-4'-carboxamide 23 using a two step chiral SFC separation.
  • the mixture was separated into two peaks containg a mixture of two diastereomers ((3' R ,4' S )-1'-(6-amino-5-fluoropyrimidin-4-yl)-3-((3-chloro-5-(trifluoromethyl)phenyl)amino)- N,N -dimethyl-2-oxo-[1,3'-bipiperidine]-4'-carboxamide and (3' S ,4' R )-1'-(6-amino-5-fluoropyrimidin-4-yl)-3-((3-chloro-5 - (trifluoromethyl)phenyl)amino)- N , N -dimethyl-2-oxo-[1,3'-bipiperidine]-4'-carboxamide) using a ChiralPak IC(2 x 15 cm, 30% methanol w/0.1 DEA) column, and then the resulting mixture containing a pair of isomers was further
  • the title compound was obtained from chiral separation of trans -1'-(6-amino-5-fluoropyrimidin-4-yl)-3-((3-chloro-5-(trifluoromethyl)phenyl)amino)- N , N- ethyl-2-oxo-[1,3'-bipiperidine]-4'-carboxamide 23 using a two step chiral SFC separation.
  • BTK-POLYGAT-LS ASSAY In vitro BTK kinase assay: BTK-POLYGAT-LS ASSAY.
  • the purpose of the BTK in vitro assay was to determine compound potency against BTK through the measurement of IC 50 .
  • Compound inhibition was measured after monitoring the amount of phosphorylation of a fluorescein-labeled polyGAT peptide (Invitrogen PV3611) in the presence of active BTK enzyme (Upstate 14-552), ATP, and inhibitor.
  • the BTK kinase reaction was done in a black 96 well plate (costar 3694).
  • a 24 uL aliquot of an ATP/peptide master mix (final concentration; ATP 10 uM, polyGAT 100 nM) in kinase buffer (10 mM Tris-HCl pH 7.5, 10 mM MgCl 2 , 200 uM Na 3 PO 4 , 5 mM DTT, 0.01% Triton X-100, and 0.2 mg/ml casein) was added to each well.
  • kinase buffer 10 mM Tris-HCl pH 7.5, 10 mM MgCl 2 , 200 uM Na 3 PO 4 , 5 mM DTT, 0.01% Triton X-100, and 0.2 mg/ml casein
  • the assay was incubated for 30 minutes before being stopped with 28 uL of a 50 mM EDTA solution. Aliquots (5 uL) of the kinase reaction were transferred to a low volume white 384 well plate (Corning 3674), and 5 uL of a 2X detection buffer (Invitrogen PV3574, with 4 nM Tb-PY20 antibody, Invitrogen PV3552) was added. The plate was covered and incubated for 45 minutes at room temperature. Time resolved fluorescence (TRF) on Molecular Devices M5 (332 nm excitation; 488 nm emission; 518 nm fluorescein emission) was measured. IC 50 values were calculated using a four parameter fit with 100% enzyme activity determined from the DMSO control and 0% activity from the EDTA control.
  • TRF Time resolved fluorescence
  • the cardiac potassium channel, hERG is responsible for a rapid delayed rectifier current (I Kr ) in human ventricle and inhibition of I kr is the most common cause of cardiac action potential prolongation by non-cardiac drugs (see, e.g., Weirich and Antoni, Basic Res. Cardiol., 93, Suppl. 1, 125-32, 1998 ; Yap and Camm, Clin. Exp. Allergy, 29, Suppl. 3, 174-81, 1999 ).
  • Increased action potential duration has been cited as a factor in causing prolongation of the QT interval that has been associated with a dangerous ventricular arrhythmia, torsade de pointes ( Brown and Rampe, Pharmaceutical News, 7, 15-20, 2000 ).
  • hERG human ether-à-go-go-related gene
  • I Kr the rapidly activating, delayed rectifier cardiac potassium current
  • HEK293 human embryonic kidney
  • Test compound (final concentration 10 uM) is incubated with either human or rat liver microsomes (final concentration 1 mg/mL), along with activating cofactors NADPH (final concentration 1 mM), potassium phosphate (final concentration 100 mM pH 7.4), magnesium chloride (final concentration 3.3 mM) and the trapping agent GSH (final concentration 5 mM).
  • the incubation mixture is incubated for 60 min at 37 °C and terminated with ice cold acetonitrile (equal volume as incubation mixture) and the supernatents isolated.
  • the supernatants are either injected directly for LC/MS/MS analysis or dried under N 2 and reconstituted in water:acetonitrile (80:20) mixture before LC/MS/MS analysis analysis.
  • the corresponding GSH conjugate is evaluated via LC/MS/MS, using a Triple TOF5600/Xevo Qtof MSe.
  • the collagen induced arthritis (CIA) model in female Lewis rats requires primary T and B cell immune responses to type II collagen (CII) immunization for the development of a severe inflammatory disease (see Goldschmidt TJ, Holmdahl R. Cell Immunol. 154(1):240-8, 1994 ; Helfgott, S. M., et al,; Clin. Immunol. Immunopathol. 31:403, 1984 ; Holmdahl R. et al., J Autoimmun. 7(6):739-52, 1994 ; and Stuart, J. M., et al., J. Exp. Med. 155:1, 1982 ). Clinical disease onsets after a secondary CII challenge and the disease progresses over the following eight days.
  • Rat Lewis rats are immunized with bovine collagen type II in incomplete Freund's adjuvant.
  • Rats receive daily oral administration of test compound or vehicle BID by oral gavage beginning on day 1 (therapeutic).
  • Clinical severity of arthritis is assessed by caliper measurements of ankles taken every day beginning on Day 0.
  • Female Lewis rats are immunized subcutaneously with bovine collagen type II (1:1 emulsion of 2 mg/ml bovine CII in 0.01 N acetic acid: Incomplete Freund's Adjuvant) at three sites of back skin.
  • Six days post immunization rats receive a second subcutaneous injection of bovine CII.
  • Clinical severity of CIA is assessed by caliper measurements of ankles taken every day beginning on Day 9. Baseline ankle caliper measurements are taken and confirmed as clinically normal (0.260-0.264 in) for prophylactic treatment.
  • Ramos cells are incubated in 96 well plates with a range of concentrations of a compound of formula I for 2 hours, stimulated with 10 ⁇ g/mL anti-IgM for 5 minutes, and PLCy2 phosphorylation measured using an electrochemical-luminescent immunoassay.
  • the EC 50 is calculated using GraphPad Prism software.
  • Human B cells are isolated from peripheral blood mononuclear cells or unpurified buffy coats using Ficoll-Hypaque gradients (Amersham) and negatively selected by magnetic cell sorting (Human B Cell Isolation Kit II, Miltenyi Biotec). Target cell purity is determined by flow cytometry by staining for markers of B cells, T cells and monocytes (CD19, CD3, CD14, respectively; BD Biosciences). Data are collected on a FACsCaliber flow cytometer and analyzed using FloJo software (BD Biosciences). Purity of human B cell preparations is routinely greater than 95%.
  • macrophages are cultured in plates previously incubated with purified IgG then washed. Titrations of test compound (10,000 nM to 0 nM) are added to these cultures. Cell culture supernatants are analyzed by ELISA for the expression of TNF ⁇ and IL-6.
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Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2473049B1 (en) 2009-09-04 2018-11-28 Biogen MA Inc. Bruton's tyrosine kinase inhibitors
EP2632898A4 (en) 2010-10-29 2014-04-02 Biogen Idec Inc HETEROCYCLIC TYROSINE KINASE HEMMER
AR091273A1 (es) 2012-06-08 2015-01-21 Biogen Idec Inc Inhibidores de pirimidinil tirosina quinasa
EP2858500A4 (en) * 2012-06-08 2016-04-06 Biogen Ma Inc INHIBITORS OF BRUTON TYROSINE KINASE
RS57662B1 (sr) * 2013-12-11 2018-11-30 Biogen Ma Inc Biaril jedinjenja korisna za lečenje humanih bolesti u onkologiji, neurologiji i imunologiji
WO2015151006A1 (en) 2014-03-29 2015-10-08 Lupin Limited Substituted purine compounds as btk inhibitors
WO2015170266A1 (en) 2014-05-07 2015-11-12 Lupin Limited Substituted pyrimidine compounds as btk inhibitors
AR102426A1 (es) * 2014-10-24 2017-03-01 Bristol Myers Squibb Co Compuestos de indolcarboxamida como inhibidores de btk
EP3487852A1 (en) * 2016-07-21 2019-05-29 Biogen MA Inc. Succinate forms and compositions of bruton's tyrosine kinase inhibitors
WO2019208805A1 (ja) 2018-04-27 2019-10-31 小野薬品工業株式会社 Ｂｔｋ阻害活性を有する化合物を有効成分として含む自己免疫疾患の予防および／または治療剤
CA3108065A1 (en) 2018-07-31 2020-02-06 Loxo Oncology, Inc. Spray-dried dispersions, formulations, and polymorphs of (s)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1h-pyrazole-4-carboxamide
US20220143049A1 (en) 2019-03-21 2022-05-12 Onxeo A dbait molecule in combination with kinase inhibitor for the treatment of cancer
JP2023500906A (ja) 2019-11-08 2023-01-11 インサーム（インスティテュ ナシオナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシェ メディカル） キナーゼ阻害剤に対する獲得抵抗性を有するがんの処置方法
WO2021148581A1 (en) 2020-01-22 2021-07-29 Onxeo Novel dbait molecule and its use
WO2022140246A1 (en) 2020-12-21 2022-06-30 Hangzhou Jijing Pharmaceutical Technology Limited Methods and compounds for targeted autophagy
WO2022212893A1 (en) 2021-04-02 2022-10-06 Biogen Ma Inc. Combination treatment methods of multiple sclerosis
WO2023081715A1 (en) 2021-11-03 2023-05-11 Viracta Therapeutics, Inc. Combination of car t-cell therapy with btk inhibitors and methods of use thereof
WO2023081709A1 (en) 2021-11-03 2023-05-11 Viracta Therapeutics, Inc. Vecabrutinib for the treatment of graft-versus-host disease
WO2023110970A1 (en) 2021-12-14 2023-06-22 Netherlands Translational Research Center Holding B.V Macrocyclic btk inhibitors

Family Cites Families (56)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1624A (en) * 1840-06-10 Cooking-stove
US4528138A (en) 1984-06-20 1985-07-09 E. R. Squibb & Sons, Inc. 16-Keto-17-substituted thia-17-alkyl(or alkenyl or alkynyl) androstenes
US4911920A (en) 1986-07-30 1990-03-27 Alcon Laboratories, Inc. Sustained release, comfort formulation for glaucoma therapy
FR2588189B1 (fr) 1985-10-03 1988-12-02 Merck Sharp & Dohme Composition pharmaceutique de type a transition de phase liquide-gel
ATE141502T1 (de) 1991-01-15 1996-09-15 Alcon Lab Inc Verwendung von karrageenan in topischen ophthalmologischen zusammensetzungen
US5212162A (en) 1991-03-27 1993-05-18 Alcon Laboratories, Inc. Use of combinations gelling polysaccharides and finely divided drug carrier substrates in topical ophthalmic compositions
US6309853B1 (en) 1994-08-17 2001-10-30 The Rockfeller University Modulators of body weight, corresponding nucleic acids and proteins, and diagnostic and therapeutic uses thereof
PA8474101A1 (es) 1998-06-19 2000-09-29 Pfizer Prod Inc Compuestos de pirrolo [2,3-d] pirimidina
US6919178B2 (en) 2000-11-21 2005-07-19 Sunesis Pharmaceuticals, Inc. Extended tethering approach for rapid identification of ligands
BR0109467A (pt) 2000-03-17 2003-06-03 Bristol Myers Squibb Pharma Co Composto derivados de (beta)-aminoácidos cìclicos, composição farmacêutica, método de tratamento de condições ou doenças mediadas por mps, tnf, aggrecanase ou uma combinação destes em mamìferos e uso de composto
MY145722A (en) 2000-04-27 2012-03-30 Abbott Lab Diazabicyclic central nervous system active agents
ATE423120T1 (de) 2000-06-26 2009-03-15 Pfizer Prod Inc Pyrroloä2,3-düpyrimidin verbindungen als immunosuppressive wirkstoffe
PE20020507A1 (es) * 2000-10-17 2002-06-25 Schering Corp Compuestos no-imidazoles como antagonistas del receptor histamina h3
AU2002363236A1 (en) * 2001-10-30 2003-05-12 Millennium Pharmaceuticals, Inc. Compounds, pharmaceutical compositions and methods of use therefor
EP1442039A1 (en) 2001-10-31 2004-08-04 Bayer HealthCare AG Pyrimido (4,5-b) indole derivatives
DK1599468T3 (da) 2003-01-14 2008-02-04 Arena Pharm Inc 1,2,3-trisubstituerede aryl- og heteroarylderivater som modulatorer af metabolisme og forebyggelse og behandling af forstyrrelser forbundet dermed såsom diabetes og hyperglykæmi
DE602004022318D1 (de) 2003-10-14 2009-09-10 Supergen Inc Proteinkinaseinhibitoren
EP1778298A4 (en) * 2004-04-01 2010-03-31 Univ Pennsylvania LIPOPROTEIN-NANO PLATFORMS
WO2005117909A2 (en) 2004-04-23 2005-12-15 Exelixis, Inc. Kinase modulators and methods of use
FR2870541B1 (fr) 2004-05-18 2006-07-14 Proskelia Sas Derives de pyrimidines antigonistes du recepteur de la vitronectine
AR050865A1 (es) 2004-09-09 2006-11-29 Sanofi Aventis Derivados de 2- morfolino-4-pirimidona
PT1812440E (pt) * 2004-11-04 2011-01-25 Vertex Pharma Pirazolo[1,5-a]pirimidinas úteis enquanto inibidores de proteínas cinases
NZ555320A (en) 2004-12-03 2010-11-26 Schering Corp Substituted piperazines as CB1 antagonists
US7994172B2 (en) 2004-12-28 2011-08-09 Exelixis, Inc. [1H-pyrazolo[3, 4-D]pyrimidin-4-yl]-piperidine or -piperazine compounds as serine-theoronine kinase modulators (P70s6k, Atk1 and Atk2) for the treatment of immunological, inflammatory and proliferative diseases
WO2006071875A1 (en) 2004-12-29 2006-07-06 Millennium Pharmaceuticals, Inc. Compounds useful as chemokine receptor antagonists
US7423043B2 (en) 2005-02-18 2008-09-09 Lexicon Pharmaceuticals, Inc. 4-Piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine compounds
US20060281700A1 (en) 2005-06-10 2006-12-14 Baumann Christian A Synergistic modulation of flt3 kinase using aminopyrimidines kinase modulators
US20060281764A1 (en) 2005-06-10 2006-12-14 Gaul Michael D Aminopyrimidines as kinase modulators
TW200740779A (en) 2005-07-22 2007-11-01 Mitsubishi Pharma Corp Intermediate compound for synthesizing pharmaceutical agent and production method thereof
PT1951684T (pt) 2005-11-01 2016-10-13 Targegen Inc Inibidores de cinases de tipo biaril-meta-pirimidina
JP2009521445A (ja) * 2005-12-21 2009-06-04 シェーリング コーポレイション Ｈ３アンタゴニスト／逆アゴニストと食欲抑制剤との組み合わせ
US20080076924A1 (en) 2006-06-30 2008-03-27 Patrick Betschmann Piperazines as P2X7 antagonists
WO2008012635A2 (en) 2006-07-26 2008-01-31 Pfizer Products Inc. Amine derivatives useful as anticancer agents
JP2009544732A (ja) 2006-07-26 2009-12-17 ノバルティス アクチエンゲゼルシャフト ウンデカプレニルピロホスフェートシンターゼの阻害剤
US20100160292A1 (en) 2006-09-11 2010-06-24 Cgi Pharmaceuticals, Inc Kinase Inhibitors, and Methods of Using and Identifying Kinase Inhibitors
BRPI0622054B8 (pt) 2006-09-22 2021-05-25 Oxford Amherst Llc composto e composição farmacêutica
CN101674831A (zh) * 2007-03-02 2010-03-17 先灵公司 用于治疗糖尿病或疼痛的哌啶基哌啶和哌嗪基哌啶
EP2125819B1 (en) 2007-03-21 2014-10-22 Bristol-Myers Squibb Company Fused heterocyclic compounds useful for the treatment of proliferative, allergic, autoimmune or inflammatory diseases
WO2008144253A1 (en) 2007-05-14 2008-11-27 Irm Llc Protein kinase inhibitors and methods for using thereof
CN101932580B (zh) 2007-06-01 2013-05-22 葛兰素史密丝克莱恩有限责任公司 咪唑并吡啶激酶抑制剂
WO2009098144A1 (en) 2008-02-05 2009-08-13 F. Hoffmann-La Roche Ag Novel pyridinones and pyridazinones
ES2542066T3 (es) 2008-04-29 2015-07-30 Immunexcite, Inc. Composiciones inmunomoduladoras y métodos de uso de las mismas
MX2011000661A (es) * 2008-07-16 2011-05-25 Pharmacyclics Inc Inhibidores de tirosina cinasa de bruton para el tratamiento de tumores solidos.
WO2010068788A1 (en) * 2008-12-10 2010-06-17 Cgi Pharmaceuticals, Inc. Heterocyclic amides as btk inhibitors
JP5487214B2 (ja) * 2008-12-19 2014-05-07 ブリストル−マイヤーズ スクイブ カンパニー キナーゼ阻害剤として有用なカルバゾールカルボキシアミド化合物
WO2010080712A2 (en) * 2009-01-06 2010-07-15 Dana Farber Cancer Institute Pyrimido-diazepinone kinase scaffold compounds and methods of treating disorders
EP2435442B1 (de) 2009-05-25 2016-01-13 Sandoz AG Verfahren zur herstellung von ceftobiprol medocaril
EP2485589A4 (en) 2009-09-04 2013-02-06 Biogen Idec Inc HETEROARYARY INHIBITORS OF BTK
EP2473049B1 (en) 2009-09-04 2018-11-28 Biogen MA Inc. Bruton's tyrosine kinase inhibitors
US8685880B2 (en) 2010-06-30 2014-04-01 Chevron U.S.A. Inc. On-site drying of aqueous salt for ionic liquid make-up
EP2632898A4 (en) 2010-10-29 2014-04-02 Biogen Idec Inc HETEROCYCLIC TYROSINE KINASE HEMMER
AR091273A1 (es) * 2012-06-08 2015-01-21 Biogen Idec Inc Inhibidores de pirimidinil tirosina quinasa
EP2858500A4 (en) 2012-06-08 2016-04-06 Biogen Ma Inc INHIBITORS OF BRUTON TYROSINE KINASE
RS57662B1 (sr) 2013-12-11 2018-11-30 Biogen Ma Inc Biaril jedinjenja korisna za lečenje humanih bolesti u onkologiji, neurologiji i imunologiji
EP3444251B1 (en) 2013-12-11 2023-06-07 Biogen MA Inc. Biaryl compounds useful for the treatment of human diseases in oncology, neurology and immunology
US20170298446A1 (en) 2014-10-03 2017-10-19 Ohio State Innovation Foundation Biomarkers of bruton tyrosine kinase inhibitor resistance

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
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AU2019203476B2 (en) 2021-01-28
PH12014502699A1 (en) 2015-02-02
US20210017155A1 (en) 2021-01-21
AU2017201536B2 (en) 2019-03-07
HK1209284A1 (zh) 2016-04-01
TWI592406B (zh) 2017-07-21
US10618887B2 (en) 2020-04-14
JP2017193583A (ja) 2017-10-26
EA201492056A1 (ru) 2015-05-29
HRP20181294T1 (hr) 2018-10-05
BR112014030655B1 (pt) 2021-04-20
AU2021202412A1 (en) 2021-05-20
PT2858499T (pt) 2018-10-24
JP2021073299A (ja) 2021-05-13
BR112014030655A2 (pt) 2017-06-27
MX2014015044A (es) 2015-09-22
CY1120638T1 (el) 2019-12-11
CN109305959B (zh) 2022-02-08
KR20220154850A (ko) 2022-11-22
JP6214643B2 (ja) 2017-10-18
TWI792158B (zh) 2023-02-11
IL235938A0 (en) 2015-02-01
PH12014502699B1 (en) 2015-02-02
WO2013185084A1 (en) 2013-12-12
RS57978B1 (sr) 2019-01-31
BR122021002178B1 (pt) 2022-03-22
ES2834333T3 (es) 2021-06-17
TWI719209B (zh) 2021-02-21
TW201805279A (zh) 2018-02-16
SI2858499T1 (sl) 2018-10-30
MX2019003618A (es) 2019-07-18
US9394277B2 (en) 2016-07-19
BR112014030655A8 (pt) 2018-01-02
IN2014DN10576A (zh) 2015-08-28
IL235938B (en) 2020-10-29
KR20210072139A (ko) 2021-06-16
LT2858499T (lt) 2018-09-10
CN104540385A (zh) 2015-04-22
SG10201708535UA (en) 2017-11-29
AU2013271407A1 (en) 2015-01-22
EP3385263B1 (en) 2020-07-22
AU2017201536A1 (en) 2017-03-23
EP2858499A1 (en) 2015-04-15
CN109305959A (zh) 2019-02-05
US20190047986A1 (en) 2019-02-14
IL277951A (en) 2020-11-30
KR102102587B1 (ko) 2020-04-22
US9944622B2 (en) 2018-04-17
SG11201408173WA (en) 2015-01-29
CN104540385B (zh) 2018-06-05
TW201410668A (zh) 2014-03-16
US20150158843A1 (en) 2015-06-11
JP2023052415A (ja) 2023-04-11
MX363672B (es) 2019-03-29
JP2015518903A (ja) 2015-07-06
EP3753934A1 (en) 2020-12-23
AR091273A1 (es) 2015-01-21
JP2019077728A (ja) 2019-05-23
CA3108186A1 (en) 2013-12-12
EA201790418A1 (ru) 2017-11-30
EP3385263A1 (en) 2018-10-10
JP2021073298A (ja) 2021-05-13
TW202142535A (zh) 2021-11-16
PH12018501463A1 (en) 2019-03-04
HUE039897T2 (hu) 2019-02-28
AU2019203476A1 (en) 2019-06-06
AU2022275504A1 (en) 2023-01-05
CA2875799A1 (en) 2013-12-12
AU2013271407B2 (en) 2016-12-08
KR102468430B1 (ko) 2022-11-21
PL2858499T3 (pl) 2019-03-29
DK2858499T3 (en) 2018-08-20
US20160304494A1 (en) 2016-10-20
CA2875799C (en) 2021-03-23
US20230174511A1 (en) 2023-06-08
CN113549055A (zh) 2021-10-26
ES2684268T3 (es) 2018-10-02
NZ702715A (en) 2016-11-25
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